PROJECT SUMMARY Rachel Kelly, PhD, MPH is a molecular epidemiologist with a focus on the metabolomics of respiratory diseases, whose overarching career goal is to become an independent researcher with the skills set to utilize integrative omic techniques for the improved biological understanding and clinical management of asthma; one of the most common chronic disorders in both adults and children worldwide. The proposed research combines her extensive experience in metabolomics with training in Whole Genome Sequencing (WGS), advanced integrative omic methods and statistics, in order to address the issue of the heterogeneous nature of asthma, which can lead to suboptimal management strategies in certain subgroups of asthmatic individuals. Evidence suggests there are multiple asthma endotypes, with distinct functional and/or pathobiological mechanisms. The hypothesis of this proposal is that asthma endotypes are best defined based on underlying omic profiles; which provide crucial insights into underlying disease mechanisms, rather than on clinical characteristics. This will be explored by leveraging existing data on 620 children with asthma from the Childhood Asthma Management Program through (aim1) utilizing clustering techniques to subset individuals with asthma into distinct omic-based endotypes (metabolic, transcriptomic and multi-omic) (aim2) interrogating the clinical features and genetic drivers of the omic endotypes; and (aim3) validating the findings in an independent population of children with asthma (the Genetic Epidemiology of Asthma in Costa Rica Study). The innovative research plan, which utilizes novel methodologies and both targeted and untargeted approaches, will represent the first study to integrate WGS, transcriptomics and metabolomics in the exploration of asthma. It is accompanied by a training and research plan, which will provide Dr. Kelly with the skills to complete the research aims, as well as the experience to transition to independence and to submit multiple R01s expanding upon the concept of asthma endotypes as a move toward precision medicine. In particular Dr. Kelly has four career goals which build upon her existing reputation in asthma metabolomics to; (1) expand her integrative omics-skills set; (2) strengthen her knowledge of genetics and genomics; (3) gain experience and expertise in the handling; processing; quality control, analysis and interpretation of WGS data; (4) gain a thorough understanding of the clinical phenotyping of asthma; and (5) deepen her understanding of study design, mentoring and the ethics of scientific research. She is supported by a diverse mentoring team, with complementary skillsets and long successful mentoring careers which, together with her experience and training, guarantee the success of this proposal. The findings will pave the way for the development of biomarkers, targeted therapeutics and personalized approaches, while exploring a novel methodology to address one of the most important analytic challenges in the field today: the integration of multiple omic data types.